HRP20190716T1 - Sustav za primjenu lijeka za kontracepciju koji se sastoji od jezgre i omotača - Google Patents
Sustav za primjenu lijeka za kontracepciju koji se sastoji od jezgre i omotača Download PDFInfo
- Publication number
- HRP20190716T1 HRP20190716T1 HRP20190716TT HRP20190716T HRP20190716T1 HR P20190716 T1 HRP20190716 T1 HR P20190716T1 HR P20190716T T HRP20190716T T HR P20190716TT HR P20190716 T HRP20190716 T HR P20190716T HR P20190716 T1 HRP20190716 T1 HR P20190716T1
- Authority
- HR
- Croatia
- Prior art keywords
- core
- pharmaceutical ingredients
- polyurethane
- shell
- active pharmaceutical
- Prior art date
Links
- 238000012377 drug delivery Methods 0.000 title 1
- 229920002635 polyurethane Polymers 0.000 claims 7
- 239000004814 polyurethane Substances 0.000 claims 7
- 239000008186 active pharmaceutical agent Substances 0.000 claims 4
- 125000001931 aliphatic group Chemical group 0.000 claims 4
- 239000005038 ethylene vinyl acetate Substances 0.000 claims 2
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 claims 2
- -1 prohormones Substances 0.000 claims 2
- 229940121948 Muscarinic receptor antagonist Drugs 0.000 claims 1
- RJKFOVLPORLFTN-LEKSSAKUSA-N Progesterone Chemical class C1CC2=CC(=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H](C(=O)C)[C@@]1(C)CC2 RJKFOVLPORLFTN-LEKSSAKUSA-N 0.000 claims 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 claims 1
- 238000010521 absorption reaction Methods 0.000 claims 1
- 229940035676 analgesics Drugs 0.000 claims 1
- 229940035674 anesthetics Drugs 0.000 claims 1
- 239000000730 antalgic agent Substances 0.000 claims 1
- 239000003242 anti bacterial agent Substances 0.000 claims 1
- 239000003429 antifungal agent Substances 0.000 claims 1
- 229940121375 antifungal agent Drugs 0.000 claims 1
- 239000000427 antigen Substances 0.000 claims 1
- 102000036639 antigens Human genes 0.000 claims 1
- 108091007433 antigens Proteins 0.000 claims 1
- 239000002246 antineoplastic agent Substances 0.000 claims 1
- 239000003443 antiviral agent Substances 0.000 claims 1
- 125000003118 aryl group Chemical group 0.000 claims 1
- 239000000812 cholinergic antagonist Substances 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 229940127089 cytotoxic agent Drugs 0.000 claims 1
- 229940011871 estrogen Drugs 0.000 claims 1
- 239000000262 estrogen Substances 0.000 claims 1
- 239000003193 general anesthetic agent Substances 0.000 claims 1
- 239000005556 hormone Substances 0.000 claims 1
- 229940088597 hormone Drugs 0.000 claims 1
- 239000004615 ingredient Substances 0.000 claims 1
- 238000009434 installation Methods 0.000 claims 1
- 230000008018 melting Effects 0.000 claims 1
- 238000002844 melting Methods 0.000 claims 1
- 210000003205 muscle Anatomy 0.000 claims 1
- 239000000583 progesterone congener Substances 0.000 claims 1
- 239000000021 stimulant Substances 0.000 claims 1
- 229940044953 vaginal ring Drugs 0.000 claims 1
- 239000006213 vaginal ring Substances 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
- A61K9/0036—Devices retained in the vagina or cervix for a prolonged period, e.g. intravaginal rings, medicated tampons, medicated diaphragms
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
- A61F6/00—Contraceptive devices; Pessaries; Applicators therefor
- A61F6/06—Contraceptive devices; Pessaries; Applicators therefor for use by females
- A61F6/14—Contraceptive devices; Pessaries; Applicators therefor for use by females intra-uterine type
- A61F6/142—Wirelike structures, e.g. loops, rings, spirals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/567—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in position 17 alpha, e.g. mestranol, norethandrolone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
- A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
- A61K31/569—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone substituted in position 17 alpha, e.g. ethisterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0092—Hollow drug-filled fibres, tubes of the core-shell type, coated fibres, coated rods, microtubules or nanotubes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Reproductive Health (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Gynecology & Obstetrics (AREA)
- Urology & Nephrology (AREA)
- Heart & Thoracic Surgery (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Biomedical Technology (AREA)
- Vascular Medicine (AREA)
- Nanotechnology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Endocrinology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Claims (15)
1. Naprava koja sadrži:
(a) jezgru, te navedena jezgra sadrži najmanje 50 % poliuretana;
(b) omotač, navedeni omotač uglavnom ili potpuno okružuje navedenu jezgru, te navedeni omotač sadrži kopolimer etilen vinil acetata; i
(c) jedan ili više aktivnih farmaceutskih sastojaka otopljenih ili dispergiranih u navedenoj jezgri i/ili navedenom omotaču.
2. Naprava prema zahtjevu 1, naznačena time što su aktivni farmaceutski sastojci odabrani iz skupine koju čine antibakterijska sredstva, antivirusna sredstva, antigljivična sredstva, kemoterapeutska sredstva, hormoni, prohormoni, anestetici, analgetici, protutijela, antigeni, mišićni stimulansi, psihoaktivni spojevi, anti-kolinergička sredstva i njihove kombinacije.
3. Naprava prema bilo kojem od zahtjeva 1-2, naznačena time što su aktivni farmaceutski sastojci prisutni u jezgri, poželjno u koncentraciji ispod njihove koncentracije zasićenja.
4. Naprava prema bilo kojem od zahtjeva 1-3, naznačena time što sadrži estrogen.
5. Naprava prema bilo kojem od zahtjeva 1-3, naznačena time što sadrži progestin.
6. Naprava prema bilo kojem od zahtjeva 1-5, naznačena time što kopolimer etilen vinil acetat ima sadržaj vinil acetata koji iznosi od 1 do 50 % m/m, poželjno od 10 do 40 m/m.
7. Naprava prema bilo kojem od zahtjeva 1-6, naznačena time što omotač ima debljinu koja iznosi od 5 do 500 µm, poželjno od 50 do 200 µm.
8. Naprava prema bilo kojem od zahtjeva 1-7, naznačena time što poliuretan sadržan u jezgri je hidrofilni alifatski poliuretan i/ili aromatski poliuretan.
9. Naprava prema zahtjevu 8, naznačena time što hidrofilni alifatski poliuretan ima apsorpciju vode u rasponu od 5 do 40 masenih %.
10. Naprava prema zahtjevu 8, naznačena time što hidrofilni alifatski poliuretan ima čvrstoću prema Shore-u od 50 do 95 A mjereno durometarskim testom.
11. Naprava prema zahtjevu 8, naznačena time što hidrofilni alifatski poliuretan ima talište u rasponu od 70 do 220 °C.
12. Naprava prema bilo kojem od zahtjeva 1-11, naznačena time što je naprava vaginalni prsten.
13. Naprava prema bilo kojem od zahtjeva 1-12, naznačena time što su farmaceutski sastojci inkapsulirani prije ugradnje u napravu.
14. Naprava prema bilo kojem od zahtjeva 1-13, naznačena time što u omotaču postoji jedan ili više aktivnih farmaceutskih sastojaka.
15. Uporaba naprave prema bilo kojem od zahtjeva 1 do 14, naznačena time što je za kontracepciju.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US201261598642P | 2012-02-14 | 2012-02-14 | |
| EP13705955.6A EP2814458B1 (en) | 2012-02-14 | 2013-02-13 | Drug delivery system for use in contraception comprising a core and a sheath |
| PCT/EP2013/052855 WO2013120888A2 (en) | 2012-02-14 | 2013-02-13 | Core sheath drug delivery devices |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HRP20190716T1 true HRP20190716T1 (hr) | 2019-06-14 |
Family
ID=47749791
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| HRP20190716TT HRP20190716T1 (hr) | 2012-02-14 | 2019-04-16 | Sustav za primjenu lijeka za kontracepciju koji se sastoji od jezgre i omotača |
Country Status (17)
| Country | Link |
|---|---|
| US (2) | US9132081B2 (hr) |
| EP (3) | EP2814458B1 (hr) |
| AR (1) | AR089990A1 (hr) |
| CY (1) | CY1121563T1 (hr) |
| DK (1) | DK2814458T3 (hr) |
| ES (1) | ES2730208T3 (hr) |
| HR (1) | HRP20190716T1 (hr) |
| HU (1) | HUE043105T2 (hr) |
| LT (1) | LT2814458T (hr) |
| PL (1) | PL2814458T3 (hr) |
| PT (1) | PT2814458T (hr) |
| RS (1) | RS58690B1 (hr) |
| SI (1) | SI2814458T1 (hr) |
| TR (1) | TR201906738T4 (hr) |
| TW (1) | TW201332585A (hr) |
| UY (1) | UY34625A (hr) |
| WO (1) | WO2013120888A2 (hr) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP3052084A1 (en) * | 2013-09-30 | 2016-08-10 | Universiteit Gent | Polyurethanes as oral drug delivery platform |
| US10413504B2 (en) | 2013-12-11 | 2019-09-17 | Merck Sharp & Dohme Corp. | Intravaginal ring drug delivery system |
| WO2015086489A1 (en) | 2013-12-11 | 2015-06-18 | Merck Sharp & Dohme B.V. | Drug delivery system for delivery of anti-virals |
| US10328087B2 (en) | 2015-07-23 | 2019-06-25 | Therapeuticsmd, Inc. | Formulations for solubilizing hormones |
| WO2017173044A1 (en) | 2016-04-01 | 2017-10-05 | Therapeuticsmd Inc. | Steroid hormone compositions in medium chain oils |
| RU2018133932A (ru) | 2016-04-01 | 2020-05-12 | Терапьютиксмд, Инк. | Фармацевтическая композиция стероидного гормона |
| KR102637575B1 (ko) * | 2016-10-05 | 2024-02-20 | 타이탄 파머슈티컬즈 인코퍼레이티드 | 버스트 방출이 감소된 약물 전달용 이식 가능한 장치 |
| EP3395335A1 (en) * | 2017-04-24 | 2018-10-31 | Kern Pharma, S.L. | Vaginal ring for the simultaneous release of two active ingredients |
| CN109248139A (zh) * | 2017-07-14 | 2019-01-22 | 国家卫生计生委科学技术研究所 | 复方左炔诺孕酮阴道环的制备方法和应用 |
| EP3801462A4 (en) | 2018-05-24 | 2022-03-16 | Celanese EVA Performance Polymers LLC | IMPLANTABLE DEVICE FOR EXTENDED RELEASE OF A MACROMOLECULAR DRUG COMPOUND |
| CN111989068A (zh) | 2018-05-24 | 2020-11-24 | 塞拉尼斯伊娃高性能聚合物公司 | 用于持续释放大分子药物化合物的可植入器件 |
| EP4215180A1 (en) | 2022-01-21 | 2023-07-26 | Sever Pharma Solutions | A drug delivery system |
| EP4215181A1 (en) | 2022-01-21 | 2023-07-26 | Sever Pharma Solutions | An intravaginal ring |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5972372A (en) * | 1996-07-31 | 1999-10-26 | The Population Council, Inc. | Intravaginal rings with insertable drug-containing core |
| US8481079B2 (en) * | 2004-03-24 | 2013-07-09 | Merck Sharp & Dohme B.V. | Drug delivery system based on polyethylene vinylacetate copolymers |
| MX2009005364A (es) | 2006-11-20 | 2009-06-05 | Organon Nv | Sistema de suministro de farmaco con forma helicoidal. |
| WO2008089488A2 (en) * | 2007-01-19 | 2008-07-24 | University Of Utah Research Foundation | Biodegradable intravaginal devices for delivery of therapeutics |
| EP3391874A3 (en) | 2007-02-12 | 2019-04-24 | Particle Sciences, Inc. | Delivery devices containing encapsulated and/or particle- bound active pharmaceutical ingredients |
| US20110045076A1 (en) | 2008-01-25 | 2011-02-24 | Kiser Patrick F | Linear order release polymer |
| US20100040671A1 (en) | 2008-08-12 | 2010-02-18 | Ahmed Salah U | Intravaginal Devices With a Rigid Support, Methods of Making, and Uses Thereof |
| LT2547332T (lt) | 2010-03-16 | 2018-12-10 | Titan Pharmaceuticals, Inc. | Heterogeninės implantuojamos priemonės, skirtos vaisto pristatymui |
-
2013
- 2013-02-08 TW TW102105020A patent/TW201332585A/zh unknown
- 2013-02-13 DK DK13705955.6T patent/DK2814458T3/da active
- 2013-02-13 EP EP13705955.6A patent/EP2814458B1/en active Active
- 2013-02-13 US US13/766,592 patent/US9132081B2/en active Active
- 2013-02-13 TR TR2019/06738T patent/TR201906738T4/tr unknown
- 2013-02-13 RS RS20190541A patent/RS58690B1/sr unknown
- 2013-02-13 ES ES13705955T patent/ES2730208T3/es active Active
- 2013-02-13 PT PT13705955T patent/PT2814458T/pt unknown
- 2013-02-13 EP EP23154951.0A patent/EP4212146A3/en active Pending
- 2013-02-13 UY UY0001034625A patent/UY34625A/es not_active Application Discontinuation
- 2013-02-13 HU HUE13705955A patent/HUE043105T2/hu unknown
- 2013-02-13 WO PCT/EP2013/052855 patent/WO2013120888A2/en active Application Filing
- 2013-02-13 SI SI201331436T patent/SI2814458T1/sl unknown
- 2013-02-13 PL PL13705955T patent/PL2814458T3/pl unknown
- 2013-02-13 EP EP18199580.4A patent/EP3449909A3/en not_active Withdrawn
- 2013-02-13 LT LTEP13705955.6T patent/LT2814458T/lt unknown
- 2013-02-14 AR ARP130100457A patent/AR089990A1/es unknown
-
2015
- 2015-09-15 US US14/855,187 patent/US9872829B2/en active Active
-
2019
- 2019-04-16 HR HRP20190716TT patent/HRP20190716T1/hr unknown
- 2019-04-24 CY CY20191100447T patent/CY1121563T1/el unknown
Also Published As
| Publication number | Publication date |
|---|---|
| EP2814458B1 (en) | 2019-04-10 |
| US9872829B2 (en) | 2018-01-23 |
| TR201906738T4 (tr) | 2019-05-21 |
| UY34625A (es) | 2013-09-02 |
| EP3449909A3 (en) | 2019-05-29 |
| US20130209539A1 (en) | 2013-08-15 |
| WO2013120888A2 (en) | 2013-08-22 |
| CY1121563T1 (el) | 2020-05-29 |
| EP3449909A2 (en) | 2019-03-06 |
| EP4212146A3 (en) | 2023-09-27 |
| US9132081B2 (en) | 2015-09-15 |
| US20160000706A1 (en) | 2016-01-07 |
| AR089990A1 (es) | 2014-10-01 |
| HUE043105T2 (hu) | 2019-08-28 |
| TW201332585A (zh) | 2013-08-16 |
| EP4212146A2 (en) | 2023-07-19 |
| LT2814458T (lt) | 2019-05-27 |
| ES2730208T3 (es) | 2019-11-08 |
| PT2814458T (pt) | 2019-05-30 |
| DK2814458T3 (da) | 2019-05-13 |
| WO2013120888A3 (en) | 2013-10-31 |
| EP2814458A2 (en) | 2014-12-24 |
| SI2814458T1 (sl) | 2019-06-28 |
| RS58690B1 (sr) | 2019-06-28 |
| PL2814458T3 (pl) | 2019-08-30 |
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